See attached continuation. RELEVANCE (See instructions): Split inteins are Nature's protein ligases, mediating the traceless ligation of any polypeptide chains to which they are appended. The research program focuses on a recently discovered family of split inteins that mediate this ligation process with unprecedented speed and fidelity, creating enormous potential in protein biotechnology with applications ranging from basic molecular and cell biology to the preparation of protein therapeutics. We will determine how these proteins catalyst the ligation reaction so efficiently and then use this information to develop therapeutic strategies targeting inteins and develop new technologies for manipulating the structure and function of proteins in vivo.